The present invention relates to polymeric drug formulations in the form of solid single-phase dispersions of water-soluble drugs in water-insoluble tissue-compatible polymer matrices. The present invention additionally relates to solid single-phase dispersions of water-soluble drugs in water-insoluble tissue-compatible polymer matrices that include a second, phase-disrupting polymer so that phase-separated microdomains form in the matrices, which results in the release rate of the drug from the polymer matrix being affected by the amount of the second polymer present.
The present invention also relates to methods for forming the polymeric drug formulations of the present invention in which the water-soluble drug, the water-insoluble tissue-compatible polymer and, optionally, the second phase-disrupting polymer are dissolved in a common solvent and then coprecipitated by the addition to the solution of a carefully selected non-solvent. The resulting coprecipitate is in the form of a solid single-phase dispersion of the drug and polymer with the second polymer, when present, being concentrated in phase-separated microdomains. The present invention also relates to methods for site-specific drug delivery by implanting in the body of a patient in need thereof the polymeric drug formulations of the present invention.
In the context of this invention, a water-soluble drug is defined as a hydrophilic compound with a solubility in water greater than 1 percent (w/v) and that is practically insoluble in nonpolar organic solvents such as ethyl acetate, methylene chloride, chloroform, toluene, or hydrocarbons. Peptide-based drugs represent a particularly important class of water-soluble drugs as defined here.
When such water-soluble drugs are incorporated into polymers, it is often difficult to prevent the rapid, uncontrolled release of drug in a burst-like fashion from the drug-polymer matrix. This is known as the “burst effect”. The burst effect becomes particularly noticeable at high drug loadings. Within the context of this invention, high levels of drug loading are defined as drug loadings in excess of 10 percent (w/w) based on the weight of drug contained per 100 mg of drug-polymer matrix. The term “lag effect” refers to the phenomenon that the rate of drug release from a drug-polymer matrix decreases to zero or close to zero, e.g., the release of drug stops for a certain period of time. Burst effects and lag effects are some of the commonly observed phenomena that render drug-polymer matrices unsuitable as “controlled release systems” for clinical applications.
The physical state of the drug-polymer mixture, also referred to as the morphology of the system, is an often overlooked key parameter in the design of polymeric drug delivery systems. In the context of the present invention, one can distinguish between the following fundamentally different morphological states: single-phase dispersions and multi-phase dispersions.
In single-phase dispersions the drug is dispersed within the polymeric phase on a molecular scale. Within the context of this invention, a single-phase dispersion is defined as a drug-polymer matrix that appears transparent and clear to transmitted visible light. This simple requirement indicates that the drug-polymer matrix is free of microdomains on the length-scale of visible light and therefore does not scatter transmitted visible light. The formation of a single-phase dispersion requires not only that the drug and polymer have some mutual miscibility, but requires also a method for creating a molecular dispersion of the drug within the polymeric phase. This is an important, often overlooked point: If a drug and polymer particles are simply mixed without creating a molecular dispersion of the drug in the polymer matrix, a single-phase dispersion cannot form, even if drug and polymer are mutually miscible.
In multi-phase dispersions, phase-separated domains exist within the drug-polymer matrix. In multi-phase dispersions, microdomains having dimensions on the length scale of visible light may be present. Within the context of the present invention, such dispersions are readily discerned by the property that the drug-polymer matrices are translucent to visible light, but appear hazy, cloudy, or foggy. Alternatively, the drug may be present in the form of distinct particles or crystals readily discernible by microscopic examination of the drug-polymer matrix. In the extreme case, the drug may be embedded within the polymer in the form of macroscopic particles, readily visible upon inspection by the naked eye.
Hydrophobic polymer matrices of both degradable and nondegradable polymers have been studied as potential vehicles for drug delivery. Although this invention is applicable to both degradable and nondegradable polymers, the following discussion is focused on the more complex degradable systems since the theory of drug release from nondegradable systems is well-known to those skilled in the art. In addition, degradable drug release formulations are generally recognized as particularly useful as implants for the delivery of peptide drugs, which, because of their low oral bioavailabilities and short half-lives in plasma, cannot be administered by conventional oral and parenteral routes.
Release characteristics from degradable polymer matrices are influenced by several factors, the most important factors being drug loading, the physical state of the drug within the polymeric matrix, and the rate of polymer degradation and erosion as determined by the composition, morphology, and molecular structure of the polymeric matrix.
Drug loading affects the release mechanism and release rate. In the prior art, the simple case of a multi-phase dispersion in which drug particles are dispersed within the polymeric phase is well understood. Briefly, at low loadings, individual drug particles have no contact between each other. Water and/or drug molecules must diffuse through the polymer matrix to allow drug release, which consequently leads to slow release. Drug particles entrapped within the polymeric matrix may not be released at all until polymer degradation leads to the physic al erosion of the polymeric matrix. At high loadings, individual drug particles are in physical contact with each other and the dissolution of individual particles results in the formation of discrete pores within the polymeric matrix through which drug is released by slow diffusion (see Siegel and Langer, J. Control. Rel., 14, 153-67 (1990)).
Often, the effect of drug loading is much more complex since the loading level will influence the morphology of the drug-polymer matrix. This point is often overlooked in the prior art. If a drug is only partially miscible with the polymer, a single-phase dispersion may be formed at low loadings. However, as the loading level is raised above the limited miscibility between the drug and the polymer, multi-phase dispersions are formed. At this point, a dramatic difference in the release mechanism is usually observed. The release rates and mechanisms are particularly difficult to analyze in formulations in which some fraction of the drug forms a single-phase blend with the polymeric matrix, while another fraction is present in the form of phase-separated domains.
In the prior art it is well-known that control of particle size and homogeneity of the drug dispersion within the polymeric phase is critical in order to obtain reproducible and prolonged drug release profiles. The formulation of polymeric drug delivery devices for water-soluble drugs as defined above is especially challenging because it is difficult to obtain uniformly dispersed mixtures of such drugs within a water-insoluble polymeric phase. This is due to the fact that no single solvents are available capable of dissolving the water-soluble drug and the water-insoluble polymeric matrix simultaneously to form a homogeneous solution from which a uniformly dispersed mixture of drug and polymer may be readily recovered. For that reason, particles of a water-soluble drug are often suspended within a solution of the polymer in an organic solvent such as methylene chloride. Upon solvent casting, the discrete drug particles are embedded within the polymeric phase in a multi-phase dispersion where the exact distribution of the drug particles is difficult to control and difficult to reproduce. This technique cannot lead to the molecular dispersion of the drug within the polymeric matrix. Alternative techniques for the formulation of polymeric controlled release devices for water-soluble drugs require the simultaneous co-extrusion or co-molding of drug particles mixed with polymer particles. Such processes are known in the literature but have significant limitations, namely, the methods are only applicable to drug-polymer combinations that can be thermally processed below the decomposition temperature of the drug. In addition, these techniques result in the aggregation of drug and polymer in discrete domains that result often in undesirable release profiles.
In some cases, careful physical admixture can produce formulations having acceptable release profiles. However, such formulations have release profiles that are complex functions of drug loading levels, size and distribution of drug particles within the polymeric matrix, and the rate of polymer degradation. For example, instead of extending the duration of drug release, elevated drug loadings usually lead to significant burst effects and an increase in the rate of drug release. Thus, it is difficult to design a suitable formulation providing an immediate release of drug at a reproducible and acceptable rate, without burst or lag effects with sustained release over extended periods of time. This is but one example of the design limitations inherent in polymeric drug delivery systems in which the rate of drug release is determined by drug loading, particle size and distribution, and/or polymer degradation.
Sturesson et al., Intern. J. Pharm., 89, 235-44 (1993), added poly(ethylene glycol) (PEG) to a poly(lactic acid-co-glycolic acid) matrix to enhance the drug release rate by providing a system with a greater content of water-soluble substances in the polymer matrix, expecting the material to facilitate polymer hydrolysis and promote diffusional release of the water-soluble drug in the matrix. However, an enhanced rate of drug release was not observed.
A means by which the effects of particle size and distribution on the release profile can be minimized and by which drug release from a polymeric matrix may be controlled independent of drug loading or polymer degradation would be highly desirable.